Quinolone and naphthyridine carboxylic acids and their analogs are known antibacterial agents useful in human and animal applications, as for example aquaculture. Much work has been directed to the synthesis of derivatives thereof with the intention of obtaining compounds which exhibit improved activity against a broad spectrum of pathogens. Moreover, many such compounds have only limited solubility in water and thus exhibit reduced oral bioavailability.
Investigations of structure-activity relationship in the case of quinolones have in many instances focused on 7-substituted derivatives. Petersen et al., in European Patent Application No. 0326916, published Aug. 9, 1989, have disclosed the use of certain 7-pyrrolidine- and 7-azaspiro[4.4]nonane-substituted quinoline derivatives which are said to be useful as antibacterial agents and animal growth promoters, as well as the synthesis of 1-cyclopropyl-7-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-6-fluoro-1,4-dihydro-4 -oxo-3-quinoline carboxylic acid.
The ethyl ester of this latter compound was reported earlier by Culbertson et al. in U.S. Pat. No. 4,929,613, issued May 29, 1990, as an intermediate in the preparation of other quinolone compounds.
The Daiichi Pharmaceutical Co., Ltd., in European Patent Application No. 0357047, published Mar. 7, 1990, has disclosed certain non-oxygen-containing azaspiro-substituted quinoline derivatives useful as antibacterial agents.
Additionally, Petersen et al. have also disclosed, in German Patent Application No. 3420743, published Dec. 5, 1985, a 7-piperazinyl quinolone compound that has a p-methylene group substituted with a 1,4-dioxaspiro[4.5]decane. This compound apparently was prepared as an intermediate to other compounds of that reference.
Despite these efforts, however, there remains a need for improved derivatives of quinolones and analogs thereof, effective against a broad spectrum of microorganisms and having enhanced solubility and biological activity.